DOMINANT NEGATIVE PDGF RECEPTORS IN AIRWAY FIBROSIS

闭塞性细支气管炎（OB）是一种纤维增生性疾病， 在肺移植后， 结缔组织产物积聚在小气道内， 进行性气流阻塞，残疾，甚至死亡。 这种疾病 被认为是由于免疫介导的气道上皮损伤， 引发不受控制的纤维增生反应 血小板衍生 生长因子（PDGF），一种指导细胞迁移和复制的部分， 间充质细胞，已强烈牵连在几个 纤维增生性肺部疾病，包括OB。 我们假设 抑制PDGF可以限制气道内的纤维增生 肺移植后。 这项建议旨在阻止 这种配体在移植的气道内局部的作用， 一种显性阴性突变PDGF受体对气道的动物模型， 移植纤维化。 为了实现这一目标，我们将1）创建一系列 来自全长受体cDNA的PDGF受体缺失突变体，和测试 这些突变体具有结合配体的能力，并作为显性突变体发挥功能， 体外阴性; 2）开发基因转移系统， 突变型受体在气道上皮中的有效表达， 利用腺病毒载体，和3）测试显性阴性PDGF 受体，以其在动物模型中抑制纤维增生的能力 移植气道纤维化

Obliterative bronchiolitis (OB) is a fibroproliferative disorder seen following lung transplantation in which mesenchymal cells and their connective tissue products accumulate within small airways, causing progressive airflow obstruction, disability and often death. This disease is thought to be due to an immune mediated airway epithelial injury which initiates an uncontrolled fibroproliferative response. Platelet-derived growth factor (PDGF), a moiety which directs the migration and replication of mesenchymal cells, has been strongly implicated in several fibroproliferative pulmonary disorders, including OB. We hypothesize that inhibition of PDGF can limit the fibroproliferation within airways seen following lung transplantation. This proposal seeks to interdict the action of this ligand locally within transplanted airways by transfecting a dominant negative mutant PDGF receptor to airways of an animal model of transplant fibrosis. To accomplish this, we will 1) create a series of PDGF receptor deletion mutants from full length receptor cDNA, and test these mutants for ability to bind ligand and function as a dominant negative in vitro; 2) develop a gene transfer system which allows efficient expression of the mutant receptor in airway epithelium by utilizing an adenovirus vector, and 3) test the dominant negative PDGF receptor for its ability to inhibit fibroproliferation in an animal model of transplant airway fibrosis.